The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function

• Main Authors: Donda, A. (Author), Dumauthioz, N. (Author), Franco, F. (Author), Ho, P.-C (Author), Jaccard, A. (Author), Lepez, A. (Author), Lunt, S.Y (Author), Maldonado-Pérez, N. (Author), Martín, F. (Author), Migliorini, D. (Author), Renaud, F. (Author), Romero, P. (Author), Teoh, S.T (Author), Tschumi, B. (Author), Waridel, P. (Author), Wenes, M. (Author), Wyss, T. (Author), Yacoub Maroun, C. (Author), Zhang, L. (Author)
• Format: Article
• Language: English
• Published: Cell Press 2022
• Subjects: chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; T cell memory; tumor-infiltrating lymphocyte metabolism
• Online Access: View Fulltext in Publisher
• ISBN: 15504131 (ISSN)
• DOI: 10.1016/j.cmet.2022.03.013

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses. © 2022 The Author(s)